Postgraduate Topics in Genetics

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A fundamental property of a single animal genome sequence is the ability to give rise to diverse cell types. The control of chromatin activity and spatial arrangement of the genome - genome architecture - establishes gene expression programmes that drive cellular identity, and dysregulation can cause disease. We study how genome architecture is regulated in vivo to establish and maintain programmes of gene expression. We use the C. elegans animal model system, in which we can leverage genetics, conduct assays in specific cell types, and use microscopy and single cell profiling to study individual known cells. Our research combines multiple approaches, including high-throughput genomic assays, high-resolution imaging, genome editing, computational analyses, and RNAi screening for functional gene discovery.  

Specific projects would depend on student interest. 

I study how pathogen genome variation and evolutionary processes impacts their epidemiology and control. I have a particular interest in the dynamics of the accessory genome in bacterial populations, including antimicrobial resistance. Using a combination of microbial genomics, epidemiological approaches, and molecular microbiology, we unpick disease processes at both patient and public health levels in both high income and lower- to middle- income nation settings in collaboration with clinicians, public health practitioners, in vivo experimentalists, and mathematical modellers. I also have an interest in knowledge exchange and policy and have held various external secondments (GO-Science, SEDRIC, and UKHSA.

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We are interested in the gene regulatory networks involved in patterning the anteroposterior (head-tail) axis in bilaterian animals. We want to understand (1) the networks’ structure and regulatory logic; (2) the patterning dynamics they contribute to during embryonic development; and (3) how and why they have evolved and diverged over time. 

To make sense of the complex, dynamic behaviour of developmental patterning systems, we take an interdisciplinary approach, combining quantitative imaging, genetic perturbations, and computational modelling. Our main model system is the early Drosophila embryo. 

 Current projects include: 

•  Interrogating the robustness and scalability of early anteroposterior patterning in Drosophila. 

• Quantitative analysis of Drosophila pair-rule gene regulation at single-nucleus resolution. 

• Theoretical analysis of patterning in gene regulatory network systems with spatial interactions. 

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Our group works on natural genome sequence variation within and between species.  In particular we study speciation in species complexes, focusing on Malawi cichlid fishes and Yponomeuta moths, collecting samples in Africa and around Cambridge respectively.  We are also involved in the Darwin Tree of Life (DToL) project which aims to obtain reference genome sequences for all eukaryotic species found in Britain and Ireland, in particular in computational methods for genome assembly and in downstream data analysis including comparative analysis.  Building on DToL we have a broadening collaboration on ancient environmental DNA with Eske Willerslev in Zoology.  Most research in the group is computational, and we welcome PhD applicants with strong mathematical, statistical and/or computational skills. 

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Research in the chromosome biology group aims to explore the relationship between the structural organisation of vertebrate chromosomes and their function. Previously we have derived a minimal human chromosome, studied de novo telomere formation and genetically manipulated cultured vertebrate cells in order to study various chromosomally-associated proteins. Current research focuses on the contributions in M phase of (i)  topoisomerase II alpha – to chromosome compaction; & (ii) of TOPBP1  - in genome stability. 

Please refer to the Group's webpage for research interests.

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The MIMIC Lab is a research group led by Dr Antoine Hocher at the University of Cambridge dedicated to exploring how evolution shapes chromatin and molecular mimicry. In the lab we combine large scale computational analysis (phylogenomics, protein folding and design) with wet lab experimentations. We are located in the heart of Cambridge, in the department of Genetics.

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There is enormous genetic variation within populations in susceptibility to infectious disease. This variation is important as it determines the burden of disease, whether populations can survive disease outbreaks, and the rate at which mosquitoes transmit disease. Furthermore, by studying this variation we can understand the evolutionary arms races between hosts and parasites, and the principles of immune system evolution. We offer projects in three areas: 

• Which genes control the susceptibility of Drosophila to infection and how to they alter immune responses? 

• How do genetic differences between African populations of the mosquito Aedes aegypti affect the transmission of diseases like dengue? 

• How have rabbits have evolved resistance to pandemic viruses and how did viruses evolve to escape host resistance? 

We study the development of the germline, the immortal cell lineage that provides the continuity of life. Using Drosophila as a model, we combine developmental, genetics, microscopy, high-throughput sequencing analyses (small RNA-seq, RNA-seq, Ribo-seq) to build a systematic and unbiased understanding of diverse aspects governing germline biology in vivo. In particular, we are interested in dissecting the mechanisms protecting the germline genome against selfish DNA modules such as transposons, as well as in using germline stem cells as a model for understanding the control of stem cell self-renewal, growth, and differentiation in vivo. Projects include: 

- Protein synthesis regulation controlling stem cell self-renewal and differentiation 

- Mechanisms safeguarding genome integrity during germline development 

- Small RNA- and chromatin-mediated regulation of alternative splicing. 

Multicellular organisms produce a fascinating diversity of cellular identities and where and when specific cell types emerge can be regulated with exquisite precision. Our group uses the colourful patterns flowers produce on their petals to study the dynamics of this decision-making process because those are readily observable, highly elaborate and fulfil very important functions, from attracting pollinators to protecting floral organs from damaging UV and water loss. We combine genetic approaches with cell and molecular biology tools in a new model organism, diverse imaging techniques, modelling and behavioural experiments to understand what mechanisms cells use to make coordinated decisions, how these decisions impact plant fitness and how evolution tinkers with these processes to generate morphological biodiversity. Interested? Contact us to discuss possible projects.

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Axonal endoplasmic reticulum (ER) is remarkable. It forms a continuous network of tubules all along the axon and is therefore a potential channel for long-distance communication, and has an internal lumen that is too small to even see easily by electron microscopy (EM). These features appear important for axon survival – mutations in ER-shaping proteins can cause the axon degeneration disease, hereditary spastic paraplegia (HSP). We use Drosophila genetics and cell biology methods including live microscopy, calcium imaging and EM, of axons and synapses, to study how ER organisation arises, and its consequences for axon function. Recent findings include that reducing ER tubules lowers calcium flux and synaptic strength, and that the narrow lumen limits axial diffusion along tubules. Possible projects include single molecule imaging of luminal protein movement, exploring how the features of ER might support local or long-range signaling, or testing some predictions of our Drosophila work in mammalian axons. 

A fundamental property of all animals is the ability to achieve species-specific body size and proportions despite developmental perturbations. The molecular and cellular mechanisms underlying this robustness, and in general the regulation of organ growth, are mostly unknown, yet have important implications for evolutionary and developmental biology and regenerative medicine. We use vertebrate limb development as a model, to study how stem/progenitor cells integrate their genetic programme with external cues, leading to robust and precise organogenesis. We use sophisticated mouse genetics (and transgenic chicken soon) to induce limb growth perturbations and study local and systemic adaptative mechanisms. We combine sophisticated genetics, embryo micro-manipulation, single-cell genomics, inter-species chimeras and high-resolution lineage-tracing to discover the key cell populations involved and the molecular pathways they use to communicate. 

> Gurdon Institute webpage 

Our lab investigates the molecular mechanisms that ensure cell fate decisions occur at the right time and in the correct order. We combine human pluripotent stem cell-based models of early development with targeted genetic and epigenetic perturbations, genomics and single-cell molecular analyses, and computational modelling to uncover the principles guiding human embryogenesis.

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We are using genomics and genome engineering approaches to understand aspects of developmental gene regulation and chromatin structure in Drosophila, with a particular focus on nervous system development and early segmentation. We are particularly interested in the function of Sox-domain transcription factors, exploring aspects of functional redundancy and evolutionary conservation. 

Available projects include: 

• The genomics of Sox transcription factors 

• Sox redundancy in the developing CNS 

• Sox function in testis development 

• Conserved Sox function during invertebrate segmentation and nervous system development   

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The Pathogen Dynamics Group studies the spread, maintenance and control of infectious diseases through analytical and empirical techniques. We are an interdisciplinary group that works closely with a wide range of different disciplines including field epidemiologists, laboratory scientists, ministries of public health, and hospitals. Much of our is in resource-poor settings, which often have a disproportionate burden from infectious diseases. Details of projects are available on the group website. 

The molecular mechanisms by which chromatin exerts control over stress response is the main focus of the lab. We aim to address the following questions in individual projects: 
•    Which cellular pathways sense environmental stress/ toxins and signal to the genome? 
•    How does chromatin interpret the information about cellular health and toxic exposure determining the transcriptional response to stress? 
•    How does the transcriptional response adapt cellular phenotypes to survive the stress? 
We study these three questions in the context of cellular exposure to environmental stress as well as small-molecule therapeutics in collaboration with pharmaceutical companies. Our approaches include epi/genomics, single-cell transcriptomics, as well as genome-wide screening to identify novel components of stress-response pathways. Discovery-driven global approaches in mammalian cells are further validated by mouse genetic models. 
 

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Projects in our group focus on the evolutionary genetics and ancestry of humans and other primates. In particular, they address questions in one of two areas: 
 
1. The inference of ancestral demographic and genetic relationships between populations. These questions lie at the interface of genetics with archaeology, anthropology and history, using mathematical and computational approaches with ancient and present-day genomic data. 

2. Understanding the nature of germline mutation and the cellular genealogy in humans. De novo mutations form the source of all differences between present-day individuals and the raw material for natural selection. 
 
In both cases, this research is theoretical rather than experimental, and requires strong computational and mathematical skills as the models become complex and datasets are large.

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Chromosomal segregation along an axis of cell polarity is a hallmark of asymmetric cell divisions throughout evolution. The budding yeast S. cerevisiae is a unique model to explore spindle orientation linked to cell polarity. In budding yeast, pole-derived astral microtubules target the spindle poles asymmetrically (bud versus mother cell) orienting the spindle to intersect the bud neck. Spindle pole components are evolutionary conserved and studies in yeast have effectively predicted similar centrosome asymmetry in stem cell self-renewing divisions. We seek to bridge the mechanisms of cell polarity, spindle orientation and cell fate under cell cycle control as is only attainable at this time using budding yeast to uncover fundamental principles for establishment of centrosome asymmetry. 

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Cell polarity is essential for most cell functions and for several key developmental processes, such as cell migration, axis formation and asymmetric stem cell divisions, whereas a loss of polarity is a critical step in the formation of tumours. We are analysing how cells become polarised and how this polarity controls the organisation of the cytoskeleton and intracellular trafficking. Part of the group studies the Drosophila oocyte, since its polarity defines the anterior-posterior axis of the future embryo. The rest of the group  focus on epithelial polarity, where we are comparing secretory (the follicle cells) and absorptive epithelia (the adult midgut) in Drosophila with a typical mammalian epithelium  (mouse intestinal organoids). Much of our work depends on advanced imaging, ranging from live imaging of mRNA transport and protein secretion to super-resolution imaging of polarity factors using custom-built microscopes with adaptive optics.

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A major question in developmental biology is to understand how cellular fate decisions are regulated precisely in space and time. Fortunately, we can now begin to watch these processes occur with the use of modern imaging approaches that allow for the following of cell fate decision events and cellular rearrangements by live 3D time-lapse microscopy. This is allowing for a shift in our understanding of pattern formation in development away from static models towards models that are based on the principles of dynamical systems and statistical mechanics. We use a combination of zebrafish and chicken embryos, as well as mouse embryonic stem cells, to determine how key extracellular signals are precisely integrated at the single cell level to generate a well-proportioned body plan 

The complex genetic program that governs the development of plants has evolved over millions of years to generate the stunning diversity of morphologies that we see today. We research the evolution of plant organ development and regulation by developing mathematical models to simulate millions of years of plant evolution. Because these simulations produce a perfect ``fossil record", it is possible to study in detail how, over evolutionary time, the accumulation of mutations leads to new developmental programs that make new organs. This gives us a broader understanding of the evolutionary design principles behind plant development. We currently work on the evolution of the stem cell niche at the shoot tip, and on the evolution of petal patterning in collaboration with dr. Edwige Moyroud." 
 
Please link to: https://www.slcu.cam.ac.uk/research/vroomans-group

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Projects include: 

• Adaptive genome evolution of bacterial pathogens (particularly S. aureus, and the genus Rickettsia) 

• Interpreting genomic regions of enhanced differentiation (particularly in Mytilus mussels) 

• The evolution of reproductive isolation 
   

Research in the Zarkan laboratory is focused on understanding and combatting bacterial biofilms and antibiotic persisters, using E. coli as a model organism. Biofilms and persisters are two important aspects of antibiotic resistance. Biofilms provide structural protection for bacteria and other microorganisms against antimicrobials and the host immune system, while persistence refer to the ability of subpopulation of genetically sensitive bacteria to survive antibiotic treatment by virtue of their dormancy. Biofilms and persisters are associated clinically with treatment failure and recurrent infections. In the case of E. coli, biofilms and persisters are common in patients with urinary tract infections (UTIs) leading to recurrent UTIs.  
 

Projects include:  

• The role of tryptophanase in the formation of biofilms and persisters.   

• Bacterial membrane potential and antibiotic persistence.  

• Urinary extracellular vesicles (uEVs) and their effect on biofilms and persisters.